Synthesis\nof Amphiphilic Amino Poly-Amido-Saccharide\nand Poly(lactic) Acid Block Copolymers and Fabrication of Paclitaxel-Loaded\nMucoadhesive Nanoparticles

Drug delivery to the esophagus through systemic administration\nremains challenging, as minimal drug reaches the desired target. Local\ndelivery offers the potential for improved efficacy while minimizing\noff-target toxicities but necessitates bioadhesive properties for\nmucosal delivery. Herein, we describe the synthesis of two new mucoadhesive\namphiphilic copolymers prepared by sequential ring-opening copolymerization\nor postpolymerization click conjugation. Both strategies yield block\ncopolymers containing a hydrophilic amine-functionalized poly-amido-saccharide\nand either a hydrophobic alkyl derivatized poly-amido-saccharide or\npoly(lactic acid), respectively. The latter resulting copolymers readily\nself-assemble into spherical, ≈200 nm diameter, positively\ncharged mucoadhesive nanoparticles. The NPs entrap ultrahigh levels\nof paclitaxel via encapsulation of free paclitaxel and paclitaxel\nconjugated to a biodegradable, biocompatible poly(1,2-glycerol carbonate).\nPaclitaxel-loaded NPs rapidly enter cells, release paclitaxel, are\ncytotoxic to esophageal OE33 and OE19 tumor cells in vitro, and, importantly,\ndemonstrate improved mucoadhesion compared to conventional poly(ethylene\nglycol)-poly(lactic acid) nanoparticles to ex vivo esophageal tissue.